Effects of a Formula-Based Ketogenic Diet on Refractory Epilepsy in 1 to 3 Year-Old Patients under Classic Ketogenic Diet.

Objectives
The classic ketogenic diet (CKD) as a potential epilepsy treatment with high-fat has not good tolerability in some patients, and so many families refuse to use this diet for long term especially in children younger than 2 year. In the present study, the efficacy and tolerability of the CKD only diet were compared with CKD combined a formula-based powder in children between 1 and 3 yr with intractable epilepsy.


Materials & Methods
We randomly enrolled 45 children referred to Mofid Children's Hospital, Tehran, Iran from April 2016 to May 2017 with refractory epilepsy for CKD only (control group), and formula based CKD (experimental group) treatment. Subjects were followed up for at least six months.


Results
Most of the patients in CKD only group did not tolerate the diet and were reluctant to eat homemade foods with high fat. All families of the patients younger than 2 yr old in this group chose to discontinue CKD and pursued other options. About 33% of the families of the patients younger than 2 yr old and 41.6% of the total patients between 1-3 yr old in experimental group stayed to the end of the trial, and all of them showed more than 90% reduction in seizure frequency after 6 months. Moreover, regardless of the other variables, using formula increased the chance of responding to treatment 7.32 times.


Conclusion
A ketogenic diet using a powder ketogenic formula is effective, safe, and tolerable in infants and children with refractory seizure especially for younger patients who are reluctant to eat ketogenic homemade foods.


Introduction
Epilepsy is the most common neurologic disorder in children and 20%-25% of these patients are resistant to medical treatments which impose high expenses on the family and affects their quality of life (1,2). Other treatment options such as surgery need to have a special epileptic focus. In addition, most of the refractory seizures have genetic origins without any brain epileptic focus, and the surgery option is available only in a small number of countries (1)(2)(3)(4).
Ketogenic diet has been a well-known treatment for refractory seizures since 1972 with positive effects on patients' social and cognitive abilities (3,(5)(6)(7). However, most of the studies about ketogenic diet have been designed for children over three years old or in a wide age range group without age categorization (8)(9)(10)(11)(12). Ketogenic formula powder is a commercial product that tastes similar to infantile formula. In the first days of starting ketogenic diet during which a child often refuses solid food, this formula is simply acceptable and is a suitable alternative (9). However, there are few studies about the efficacy of the respective diet in children especially children younger than 2 yr old. Therefore, we aimed to study and compare the tolerability and efficacy of classic ketogenic diet with the powder formula in children between 1 and 3 yr of age with intractable epilepsy.

Materials & Methods
Overall, 45 children, 12- The frequency of weekly seizures was assessed in 1 st , 3 rd , and 6 th month after intervention in both groups (Table 1). About 50% seizure reduction was more prominent in KetoCal® group than CKD only group, and the difference between the two groups was statistically significant (P<0.05).
Seizure reduction between two groups was also compared based on the seizure type. In the KetoCal® group, the therapeutic response in the 3 rd and 6 th months of follow-up was quite remarkable in myoclonic seizures and infantile spasm, with a significant statistical difference (P<0.01) ( Table   2). The effect of age, gender, and type of seizure on the therapeutic response were studied. Based on the results ( However this was not seen in KetoCal® group. None of the patients were excluded from the study because of the lack of ketone production. None of the patients had biochemical disorders causing the ketogenic diet to be discontinued. The random urine Ca/Cr ration was more than 0.2 in 13 patients, treated with polycitrate-potassium.  (15)(16)(17)(18). However, CKD as a high-fat diet has not good tolerability in some patients, and many families refuse to use the diet for the long term especially in children younger than 2 yr old.
Many prospective studies that studied the effect of CKD in the treatment of epilepsy in long term have been performed in patients older than 2 yr old (19).
In the present study, the efficacy and tolerability of CKD only and formula-based CKD with Overall, the diet of 59% of parents was palatable and tolerable enough. In the present study, the response rate to the ketogenic diet was age-related as with increasing every month of age the response rate to treatment increased by 6%. However, ketogenic diet was more effective in younger patients. The researchers believe that production and utilization of ketone bodies in younger patients are better than older patients (20,21). On the other hand, the response rate to the ketogenic diet was not age-related (10). We found that in the younger patients, not only the tolerability of the ketogenic diet was poor, but also the efficacy of the diet was low. Compared to older patients, the increase of They indicated that 28.9 % of children had a greaterthan-50%-reduction of seizures and 23.7% were seizure-free during a 12-months follow-up period.
In a research study, one-third of the patients on the ketogenic diet showed more than 90% reduction in seizure. However, completely seizure-free subjects were rare (22). In another study, KetoCal® was used for children between 12 months and 5 yr old with refractory epilepsy who were reluctant to eat homemade food (8 and tonic-clonic generalized seizures was better in comparison to complex partial seizures (23).
In conclusion, a ketogenic diet using a powder formula (KetoCal®) is effective, safe, and tolerable in infants and children with refractory seizures.
Response rate to ketogenic diet is age-related.
The KetoCal® diet can be an appropriate choice especially for those younger than 2 yr old and patients who are reluctant to eat homemade food.

Acknowledgement
We hereby thank participating parents and children All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.